1	Reflections on AS – from diagnosis & genetics to future research Ellie Smith WSGP Children’s Hospital at Westmead, NSW, Australia
2	phenotype Scoring system Williams et al., 1995 A Consistent 100% developmental delay - functionally severe speech impairment – minimal / no use words movement / balance disorder - ataxic gait, tremulous movement of limbs behavioural uniqueness – laughter, smiling, happy, excitable, hypermotoric, short attention span.
3	phenotype Scoring system Williams et al., 1995 B Frequent >80% delayed growth – ↓ head circumference by 2 years of age seizures - usually < 3 years abnormal EEG – large amplitude, slow-spike waves (~2-3Hz) facilitated by eye closure
4	phenotype Scoring system Williams et al., 1995 C Associated (20-80%) flat occiput flexed uplifted arm position tongue (protruding, poor suck) prognathia, infantile feeding problems, wide mouth, widely spaced teeth, drooling, strabismus, pale skin, sleep disturbance, fascination with water, ↑ heat sensitivity
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7	5 classes of errors involving the critical region → AS Deletion UPD IM (IE, ID) UBE3A Epigenetic because of this complexity, many tests may be required for accurate diagnosis
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14	the common deletion - most bet BP1/BP2 and BP3 Usually between BP1 or 2 and BP3
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16	Imprinting defects patients with a positive methylation test but non deleted on FISH and with biparental inheritance ie non disomic on DNA have an imprinting defect - definition
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19	PWS & AS in one family
20	Ultimate Proof of Imprinting
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24	Ubiquitination
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26	AS genetic mechanisms 5 classes - summary
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28	reflections on AS Phenotype I think the scoring system is good - but not used diagnosis is still delayed no single feature is diagnostic AS rare, while “difficult” babies are common Need to increase awareness Good ways to increase awareness : have a conference : form a society : do research
29	reflections on AS Research Start UBE3A testing on our Me- patients, currently not available in Australasia Collect data for comparisons of phenotype in different genetic classes Provide information on frequency of AS
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31	reflections on AS Start an AS clinic - provide information natural history ; treatment successes / failures - eg melatonin for sleep, epilepsy medication; overlap with other syndromes ; response to certain therapies for communication ; better care
32	future research SNO RNAs - expression studies Differences in del/UPD/ID for parameters not yet looked for eg endocrine pathways, hypothalamus, hormones, sleep apnoea, appetite control, temperature control “Look alikes” – how many of them will have methylation negative AS ? Mouse models and epigenetics eg histones
33	recent research in PWS
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36	Normal
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38	Trisomy Rescue
39	Monosomy Duplication
40	CVS - AF
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